MX2008008760A - Use of organic compounds - Google Patents

Abstract

A method for improving glucose control by administering a DPP-IV inhibitor to a patient in need thereof, before or with the evening meal.

Description

USE OF ORGANIC COMPOUNDS The invention relates to a method for the treatment of a patient suffering from hyperglycemia, wherein this patient is administered vildagliptin, preferably 100 milligrams, 50 milligrams, or 25 milligrams of vildagliptin, or a salt thereof, before or after with the food of the night, or a method to reduce the production of nocturnal hepatic glucose in a patient suffering from hyperglycemia, where this patient is administered vildagliptin, preferably 100 milligrams, 50 milligrams, or 25 milligrams of vildagliptin, or a salt of it, before or with the food of the night. Preferably, a patient with type 2 diabetes and glycosylated hemoglobin of the baseline (HbAlc) > 8.0 percent. Preferred patients are suffering from hyperglycemia, such as diabetes mellitus, preferably non-insulin-dependent diabetes mellitus or Glucose Impaired Metabolism (IGM), preferably Impaired Glucose Tolerance (IGT). Diabetes mellitus is a relatively common disorder characterized by hyperglycemia. There are three basic types of diabetes mellitus, type 1 or insulin dependent diabetes mellitus (IDDM), type 2 or non-insulin dependent diabetes mellitus (NIDDM), and type A insulin resistance. Patients with type 1 diabetes or type 2 may become insensitive to the effects of exogenous insulin ("insulin resistant") through of a variety of mechanisms. Insulin resistance type A results from mutations in the insulin receptor gene, or from defects in post-receptor action sites critical for glucose metabolism. Diabetes is generally controlled through the administration of exogenous insulin (especially in type 1 diabetics), dietary control and exercise (especially in type 2 diabetics), or both. Impaired glucose metabolism (IGM) is defined by blood glucose levels that are above the normal range, but are not high enough to meet the diagnostic criteria for type 2 diabetes mellitus. The incidence of impaired metabolism of the Glucose varies from country to country, but usually occurs two to three times more frequently than overt diabetes. Until recently, it was felt that individuals with impaired glucose metabolism were pre-diabetic, but data from several epidemiological studies argue that subjects with impaired glucose metabolism are heterogeneous with respect to their risk of diabetes and their risk of pathology. and cardiovascular mortality. Among subjects with impaired glucose metabolism, approximately 58 percent have impaired glucose tolerance (IGT), another 29 percent have impaired fasting glucose (I FG), and 13 percent have abnormalities (I FG). / IGT). Impaired tolerance to glucose is characterized by elevated post-prandial (post-food) hyperglycemia, whereas impaired glucose in Fasting has been defined by the ADA based on fasting glycemic values. The categories of normal glucose tolerance (NGT), impaired glucose metabolism, and type 2 diabetes mellitus were defined by the ADA (American Diabetes Association) in 1997. The use of dipeptidyl-peptidase IV inhibitors for the treatment of hyperglycemia is a promising new therapeutic approach. Inhibitors of dipeptidyl-peptidase IV increase post-food plasma levels of intact (active) GLP-1 and GIP in patients with hyperglycemia, for example diabetes mellitus type 2, by inhibiting dipeptidyl-peptidase IV, the enzyme that degrades and inactivates these incretin hormones. Because the release of incretin hormone depends on the intake of nutrients, it could be expected that the inhibition of dipeptidyl peptidase IV would have little influence on GLP-1 or GIP in the fasted state. During the clinical development of dipeptidyl-peptidase IV inhibitors, the applicant has surprisingly discovered a method of treatment that can provide additional therapeutic benefits for the treatment of hypoglycemic patients. In fact, additional therapeutic benefits (eg, pharmacodynamic benefits) may be demonstrated if the dipeptidyl peptidase IV inhibitor is administered to the patient before or with the evening meal, preferably to a patient with type 2 diabetes and with baseline HbAlc > 8.0 percent. Accordingly, the present invention relates to: A method for the treatment of a patient suffering from hyperglycemia, wherein an inhibitor of dipeptidyl-peptidase IV or a salt thereof is administered to this patient before or with the evening meal . The use of an inhibitor of dipeptidyl-peptidase IV or a salt thereof, for the manufacture of a medicament for the treatment of hyperglycemia, wherein the inhibitor of dipeptidyl-peptidase IV is administered to this patient before or with the evening meal . A method for reducing the production of nocturnal hepatic glucose in a patient suffering from hyperglycemia, wherein an inhibitor of dipeptidyl-peptidase IV or a salt thereof is administered to this patient, before or with the evening meal. The use of an inhibitor of dipeptidyl-peptidase IV or a salt thereof, for the manufacture of a medicament for reducing the production of nocturnal hepatic glucose in a patient suffering from hyperglycemia, wherein the inhibitor of dipeptidyl-peptidase IV is administered to this patient before or with the food of the night. The methods or uses described herein, wherein: the patient is suffering from type 2 diabetes, or the patient is suffering from type 2 diabetes with baseline HbAlc > 8.0 percent.

The methods or uses described herein, wherein: the patient is suffering from impaired tolerance to glucose. The methods or uses described herein, wherein: - the dipeptidyl peptidase IV inhibitor is vildagliptin or a salt thereof, are administered between 25 milligrams and 1 00 milligrams, or between 50 milligrams and 100 milligrams of vildagliptin or a salt of it, before or with the food of the night, or - 25 milligrams, 50 milligrams, or 100 milligrams of vildagliptin or a salt of it, before or with the food of the night. A method for the treatment of a patient with type 2 diabetes, and with baseline HbAl c > 8.0 percent, where between 25 milligrams and 1 00 milligrams, or between 50 milligrams and 100 milligrams of vildagliptin (preferably, 25, 50, or 100 milligrams of vildagliptin) or a salt thereof, is administered to this patient, before or with the food of the night. The use of an inhibitor of dipeptidyl-peptidase IV or a salt thereof, for the manufacture of a medicament for the treatment of a patient with type 2 diabetes and with HbAl c of the baseline > 8.0 percent, where they are administered between 25 milligrams and 100 milligrams, or between 50 milligrams and 1 00 milligrams of vildagliptin (preferably 25, 50, or 1000 milligrams of vildagliptin) or a salt thereof to this patient, before or with the food of the night.

A method to reduce the production of nocturnal hepatic glucose in a patient with type 2 diabetes, or with HbAl c of the baseline > 8.0 percent, where between 1 00 milligrams and 50 milligrams of vildagliptin (preferably 25, 50, or 100 milligrams of vildagliptin) or a salt thereof are administered to this patient, before or with the evening meal. The use of an inhibitor of dipeptidyl peptidase IV or a salt thereof, for the manufacture of a medicament for reducing the production of nocturnal hepatic glycoside in a patient with type 2 diabetes and with HbAl c of the baseline > 8.0 percent, where they are administered between 25 milligrams and 1 00 milligrams, or between 50 milligrams and 100 milligrams of vildagliptin (preferably 25, 50, or 100 milligrams of vildagliptin) or a salt thereof to this patient, before or after with the food of the night. The methods or uses described herein, wherein a daily dosage of 100 milligrams of vildagliptin or a salt thereof is administered to the patient. The methods or uses described herein, wherein a single daily dosage of 100 milligrams of vildagliptin or a salt thereof is administered to the patient, ie, 1 00 milligrams are administered before or with the evening meal. The methods or uses described herein, wherein 50 milligrams are administered twice a day (twice a day, ie, 1000 milligrams per day) of vildagliptin or a salt thereof, and 50 milligrams are administered to the patient before or with food of the night. Preferably, the first 50 milligrams are administered before (for example, up to 1 hour before or up to 10 minutes before) breakfast or with breakfast. The methods or uses described herein, wherein 25 milligrams are administered twice a day (twice a day, ie, 50 milligrams per day) of vildagliptin or a salt thereof, and 25 milligrams are administered to the patient before or with the food of the night. Preferably, the first 25 milligrams are administered before (for example, up to 1 hour before, or up to 10 minutes before) breakfast or with breakfast. The methods or uses described herein, wherein vildagliptin or a salt thereof is administered approximately 30 minutes before dinner. The Applicant has also discovered that nighttime hepatic glucose production can be reduced in a patient with type 2 diabetes, especially with baseline HbAlc > 8.0 percent, if at least one dosage of 100 milligrams of vildagliptin or a salt thereof is administered to the patient, before or with the morning meal, or before or with lunch. Accordingly, in a further aspect, the present invention relates to a method for reducing the production of nocturnal hepatic glucose in a patient with type 2 diabetes, especially with baseline HbAlc > 8.0 percent, where at least 100 milligrams of vildagliptin are administered (preferably between 100 and 150 milligrams, or a specific dosage) of 1 00 milligrams or 1 50 milligrams of vildagliptin) or a salt thereof to this patient, before or with the morning meal, or before or with lunch. Accordingly, in a further aspect, the present invention relates to the use of vildagliptin or a salt thereof, for the manufacture of a medicament for reducing the production of nocturnal hepatic glucose in a patient with type 2 diabetes, especially with HbAl. c of the baseline > 8.0 percent, where at least 100 milligrams of vildagliptin are administered (preferably between 1 00 milligrams and 1 50 milligrams, or a specific dosage of 100 milligrams or 1 50 milligrams of vildagliptin), or a salt thereof to this patient, before or with the food in the morning, or before or with lunch. The methods or uses described herein, wherein the dipeptidyl peptidase IV inhibitor is administered in combination with metformin. Preferably with 250 milligrams, 500 milligrams, 750 milligrams, 850 milligrams, or 1, 000 milligrams of metformin. Preferably, metformin is also administered before or with the evening meal. The term "dipeptidyl peptidase IV inhibitor" is intended to indicate a molecule that exhibits inhibition of the enzymatic activity of dipeptidyl peptidase IV and functionally related enzymes, such as an inhibition of 1 aM OO percent, and especially retains the action of substrate molecules, including, but not limited to, the glucagon-1 type peptide, the inhibitory polypeptide gastric, histidine peptide methionine, substance P, neuropeptide Y, and other molecules that typically contain alanine or proline residues in the second amino-terminal position. Treatment with the dipeptidyl peptidase IV inhibitors prolongs the duration of action of the peptide substrates, and increases the levels of their intact non-degraded forms, leading to a spectrum of biological activities relevant to the invention being disclosed. The dipeptidyl peptidase IV can be used in the control of glucose metabolism, because its substrates include the insulinotropic hormones of glucagon-1 type peptide (GLP-1), and gastric inhibitory peptide (GIP). GLP-1 and GIP are active only in their intact forms; the removal of its two N-terminal amino acids inactivates them. In vivo administration of synthetic inhibitors of dipeptidyl-peptidase IV prevents N-terminal degradation of GLP-1 and GIP, resulting in higher plasma concentrations of these hormones, higher insulin secretion, and therefore, better glucose tolerance. For that purpose, the chemical compounds are tested for their ability to inhibit the enzymatic activity of purified CD26 / DPP-IV. Briefly, the activity of CD26 / DPP-IV is measured in vitro by its ability to dissociate the synthetic substrate of Gly-Pro-p-nitro-anilide (Gly-Pro-pNA). Dissociation of Gly-Pro-pNA by dipeptidyl peptidase IV releases the p-nitro-anilide product (pNA), whose appearance index is directly proportional to the activity enzymatic The inhibition of the enzymatic activity by inhibitors of specific enzymes slows down the generation of p-nitro-anilide. The stronger interaction between an inhibitor and the enzyme results in a slower p-nitro-anuide generation rate. Accordingly, the degree of inhibition of the accumulation rate of p-nitro-anilide is a direct measure of the strength of the enzyme inhibition. The accumulation of p-nitro-anilide is measured with a spectrophotometer. The inhibition constant, Ki, for each compound, is determined by incubating fixed amounts of enzyme with several different concentrations of inhibitor and substrate. In the present context, "an inhibitor of dipeptidyl peptidase IV" is also intended to comprise the active metabolites and the prodrugs thereof, such as the active metabolites and the pro-drugs of the dipeptidyl-peptidase IV inhibitors. A "metabolite" is an active derivative of dipeptidyl peptidase IV produced when the dipeptidyl peptidase IV inhibitor is metabolized. A "pro-drug" is a compound that is metabolized to an inhibitor of dipeptidyl-peptidase IV, or metabolized to the same metabolites as an inhibitor of dipeptidyl-peptidase IV. In the present context, the term "an inhibitor of dipeptidyl peptidase IV" is also intended to comprise the pharmaceutical salts thereof. Inhibitors of dipeptidyl peptidase IV are known in the art. In the following, reference is made to the representatives of the dipeptidyl-peptidase IV inhibitors: Preferred dipeptidyl peptidase IV inhibitors are described in the following patent applications: WO 02053548, especially compounds 1 001 to 1293 and Examples 1 to 124; WO 0206791 8 especially compounds 1 000 to 1278 and 2001 to 21 59; WO 02066627 especially the described examples; WO 02/068420, especially all the compounds specifically listed in Examples I to LXI II, and the corresponding analogs described, including the preferred compounds are 2 (28), 2 (88), 2 (1 1 9), 2 ( 1 36) described in the table that reports the IC50; WO 02083128, as in claims 1 to 5, especially the compounds described in Examples 1 to 13 and in claims 6 to 10; US 2003096846, especially the compounds specifically described; WO 2004/0371 81, especially Examples 1 to 33; WO 01 68603, especially the compounds of Examples 1 to 109; EP1258480, especially the compounds of Examples 1 to 60; WO 01 81337, especially Examples 1 to 1 1 8; WO 020831 09, especially Examples 1 A to 1 D; WO 030003250, especially the compounds of Examples 1 to 1 66, more preferably 1 to 8; WO 03035067; especially the compounds described in the examples; WO 03/035057, especially the compounds described in the examples; US200321 6450, especially examples 1 to 450; WO 99/46272, especially the compounds of claims 1 2, 1 4, 1 5, and 1 7; WO 01 97808, especially the compounds of claim 2; WO 03002553, especially the compounds of Examples 1 to 33; WO 01/34594, especially the compounds described in Examples 1 to 4; WO 02051 836, especially Examples 1 to 712; EP1 245568, especially Examples 1 to 7; EP1258476, especially Examples 1 to 32; US 2003087950, especially the described examples; WO 02/076450, especially Examples 1 to 128; WO 030001 80, especially Examples 1 to 1 62; WO 030001 81, especially Examples 1 to 66; WO 03004498, especially Examples 1 to 33; WO 0302942, especially Examples 1 to 68; US 6482844, especially the described examples; WO 01 55105, especially the compounds listed in Examples 1 and 2; WO 0202560, especially Examples 1 to 1 66; WO 03004496, especially Examples 1 to 103; WO 03/024965, especially Examples 1 to 54; WO 0303727, especially Examples 1 to 209; WO 0368757, especially Examples 1 to 88; WO 03074500, especially Examples 1 to 72, Examples 4.1 to 4.23, Examples 5.1 to 5.10, Examples 6.1 to 6.30, Examples 7.1 to 7.23, Examples 8.1 to 8.10, Examples 9.1 to 9.30.; WO 02038541, especially Examples 1 to 53; WO 02062764, especially Examples 1 to 293, preferably the compound of Example 95 (2- {{3- (amino-methyl) -4-butoxy-2-neopentyl-1 -oxo-1-hydrochloride. , 2-dihydro-6-isoquinolinyl, y-oxi.,. -acetamide); WO 02308090, especially Examples 1 -1 to 1 -109, Examples 2-1 to 2-9, Example 3, Examples 4-1 to 4-1 9, Examples 5-1 to 5-39, examples 6-1 to 6-4, examples 7-1 to 7-1 0, examples 8-1 to 8-8, examples 7-1 to 7-7 on page 90, examples 8-1 to 8-59 of pages 91 to 95, examples 9-1 to 9-33, examples 1-0-1 to 10-20; US2003225102, especially compounds 1 to 11, the compounds of Examples 1 to 121, preferably compounds a) to z), aa) to az), ba) to bz), ca) to cz) and da) to dk); WO 0214271, especially Examples 1 to 320; US 2003096857, U.S. Patent Application Serial Number 09 / 788,173, filed February 16, 2001 (attorney's file LA50), especially the described examples; WO99 / 38501, especially the described examples; W099 / 46272, especially the examples described, and DE19616 486 A1, especially val-pyr, val-thiazolidide, isoleucyl-thiazolidide, isoleucyl-pyrrolidide, and smoking salts of isoleucyl-thiazolidide and isoleucyl-pyrrolidide. Other preferred dipeptidyl peptidase IV inhibitors include the specific examples disclosed in U.S. Patent Nos. 6124305 and US 6107317, in International Patent Applications with Publication Numbers WO 9819998, WO 9515309 and WO 9818763.; such as 1- [2- [. { 5-ethano-pyridin-2-yl) -amino-ethyl-amino] -acetyl-2-cyano- (S) -pyrrolidine and (2S) -1 - [(2S) -2-amino-3,3-dimethyl -butanoyl] -2-pyrrolidine-carbonitrile. In a further preferred embodiment, the dipeptidyl peptidase inhibitor IV is an N-peptidyl-O-aroyl-hydroxylamine or a pharmaceutically acceptable salt thereof. Aroyl is, for example, naphthylcarbonyl; or benzoyl which is unsubstituted or mono- or disubstituted, for example, by lower alkoxy, lower alkyl, halogen, or preferably nitro. The peptidyl fraction preferably comprises two a-amino acids, for example glycine, alanine, leucine, phenyl-alanine, lysine or proline, of which one directly attached to the hydroxylamine nitrogen atom is preferably proline. In each case, in particular in the claims of compounds and in the final products of the processing examples, the subject matter of the final products, the pharmaceutical preparations and the claims, are incorporated in the present application by reference to these publications. International Publication Number WO 9819998 discloses N- (N'-substituted glycolyl) -2-cyano-pyrrolidines, in particular 1 - [2- [5-cyano-pyridin-2-yl] -amino] -ethyl -amino] -acetyl-2-cyano- (S) -pyrrolidine. The preferred compounds described in International Publication Number WO03 / 002553 are listed on pages 9 to 11, and are incorporated by reference herein. German Patent Number DE19616486 A1 discloses val-pir, val-thiazolidide, isoleucyl-thiazolidide, isoleucyl-pyrrolidide, and smoking salts of isoleucyl-thiazolidide and isoleucyl-pyrrolidide. International Publication Number WO 0034241 and U.S. Patent Number US 6110949, disclose N-substituted adamantyl-amino-acetyl pyrrolidines, and W- (substituted glycyl) -4-cyano-pyrrolidines, respectively. Inhibitors of dipeptidyl peptidase IV of interest are in particular those mentioned in claims 1 to 4. International Publication Number WO 9515309 gives know 2-cyano-pyrrolidine amides of amino acids as inhibitors of dipeptidyl-peptidase IV, and International Publication Number WO 9529691 discloses peptidyl derivatives of diesters of alpha-amino-alkyl-phosphonic acids, in particular those with proline or related structures . The dipeptidyl peptidase IV inhibitors of interest are in particular those mentioned in Tables 1 to 8. In International Publication Number WO 01/72290, the dipeptidyl peptidase IV inhibitors of interest are in particular those mentioned in Example 1, and in claims 1, 4, and 6. International Publication Number WO 9310127 discloses proline boronic esters useful as inhibitors of dipeptidyl peptidase IV. The dipeptidyl peptidase IV inhibitors of interest are especially those cited in Examples 1 to 19. Published Patent Application Number WO 9925719 discloses sulfostine, an inhibitor of dipeptidyl peptidase IV prepared by culture. of microorganism of Streptomyces. International Publication Number WO 9938501 discloses N-substituted 4 to 8 membered heterocyclic rings. The dipeptidyl peptidase IV inhibitors of interest are those recited in claims 15 to 20. International Publication Number WO 9946272 discloses phosphoric compounds as inhibitors of dipeptidyl peptidase IV. Inhibitors of dipeptidyl peptidase IV of interest are in particular those mentioned in claims 1 to 23.

Other preferred dipeptidyl peptidase IV inhibitors are compounds of Formula I, II, or III, disclosed in Patent Application Number WO 03/057200 on pages 14 to 27. The most preferred dipeptidyl peptidase IV inhibitors are the compounds specifically described on pages 28 and 29. Published Patent Applications Nos. WO 9967278 and WO 9967279 disclose propeptides and inhibitors of dipeptidyl peptidase IV of the ABC form, wherein C is a stable or unstable inhibitor. of dipeptidyl peptidase IV. Preferably, the N-peptidyl-O-aroyl-hydroxylamine is a compound of the Formula VII: (VII) where: j is 0, 1, or 2; Re! represents the side chain of a natural amino acid; and Re2 represents lower alkoxy, lower alkyl, halogen, or nitro; or a pharmaceutically acceptable salt thereof.

In a highly preferred embodiment of the invention, the N-peptidyl-O-aroyl-hydroxylamine is a compound of the Formula Vlla: or a pharmaceutically acceptable salt thereof. The N-peptidyl-O-aroyl-hydroxylamines, for example of the Formulas VII or Vlla, and their preparation, are described by HU Demuth et al., In J. Enzyme Inhibition 1988, Volume 2, pages 129-142, especially in pages 130-132. Preferred dipeptidyl peptidase IV inhibitors are those described by Mona Patel et al (Expert Opinion Investig Drugs, April 2003; 12 (4): 623-33), in paragraph 5, especially P32 / 98, K-364 , FE-999011, BDPX, NVP-DDP-728, and others, the publication of which is incorporated herein by reference, especially the dipeptidyl peptidase IV inhibitors described. Another preferred dipeptidyl peptidase IV inhibitor is number 815541 (T 8666) from Tanabe. Preferred dipeptidyl peptidase IV inhibitors are also described in International Patent Application Number WO 02/083128, especially the compounds described in Examples 1 to 13; in U.S. Patent Number US 6,395,767, Examples 1 to 109, and in International Publication Number WO 03/033871, all specifically described compounds, e.g., compounds 1 to 393, and compounds on pages 67 to 70. FE-999011 is described in International Application Number WO 95/15309, page 14, as compound number 18. Another preferred inhibitor is compound BMS-477118, which is disclosed in International Publication Number WO 2001068603 or in US Pat. No. 6,395,767 (composed of Example 60), also known as (1S, 3S, 5S) -2 - [(2S) -2-benzoate -amino-2- (3-hydroxytrichyclo- [3.3.1.13'7] -dec-1-yl) -1-oxo-ethyl] -2-azabicyclo- [3.1.0] -hexan-3-carbonitrile (1: 1), as illustrated in Formula M of International Patent Application Number WO 2004/052850 on page 2, and the corresponding free base, (1S, 3S, 5S) -2 - [(2S) -2- amino-2- (3-hydroxy-tricyclo- [3.3.1.137] -dec-1-yl) -1-oxo-ethyl] -2-azabicyclo- [3.1.0] -hexan-3-carbonitrile (M ') and its monohydrate (M "), as illustrated in Formula M of International Patent Application Number WO 2004/052850 on page 3. The compound BMS-477118 is also known as saxagliptin.Another preferred inhibitor is the compound GSK23A which is disclosed in International Publication Number WO 03/002531 (Example 9), also known as (2S, 4S) -1 - (( 2R) -2-amino-3 - [(4-methoxy-benzyl) -sulfonyl] -3-methyl-butanoyl) -4-fluoro-pyrrolidine-2-carbonitrile. P32 / 98 (CAS number: 251572-86-8), also known as 3 - [(2S, 3S) -2-amino-3-methyl-1 -oxo-pentyl] -thiazolidine, can be used as the mixture of 3 - [(2S, 3S) -2-amino-3-methyl-1-oxo-pentyl] -thiazolidine and (2E) -2-butenedione (2: 1), and is described in International Publication Number WO 99 / 61431 and in the following Formula: which is described in International Publication Number W099 / 61 431, and also in Diabetes 1 998, 47, 1 253-1258, in the name of Probiodrug, as well as compound P93 / 01 described by the same company. Other highly preferred dipeptidyl peptidase IV inhibitors are the compounds disclosed in International Patent Application Number WO 02/083128, as in claims 1 to 5. The most preferred dipeptidyl peptidase IV inhibitors are the compounds specifically described by Examples 1 to 1, and claims 6 to 10. Other highly preferred inhibitors of dipeptidyl peptidase IV are compounds disclosed by Bristol-Myers Squibb, such as Saxagliptin (BMS4771 1 8). Other highly preferred dipeptidyl peptidase IV inhibitors of the invention are described in International Publication Application No. WO 02/076450 (especially Examples 1 to 128), and by Wallace T. Ashton (Bioorganic & amp; amp;; Medicinal Chemistry Letters 1 4 (2004) 859-863), especially compound 1 and the compounds listed in Tables 1 and 2. The preferred compound is compound 21 e (Table 1) of the Formula: Other preferred dipeptidyl peptidase IV inhibitors are described in International Patent Applications Nos. 2004/037169, especially those described in Examples 1 to 48, and WO 02/062764, especially the Examples described 1 to 293, and still further Preferred are the compounds of 3- (amino-methyl) -2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinoline-carboxamide and 2-. { [3- (Amino-methyl) -2-isobutyl-4-phenyl] -1-oxo-1,2-dihydro-6-isoquinolyl] -oxi} -acetamide, described on page 7, and also in International Patent Application Number WO2004 / 024184, especially in Reference Examples 1 to 4. Other preferred dipeptidyl peptidase IV inhibitors are described in International Patent Application Number WO 03/004498, especially Examples 1 to 33, and more preferably the compound of the Formula: MK-0431 described by Example 7, and also known as MK-0431 or Sitagliptin (INN). In each case, in particular in the claims of compounds and the final products of the processing examples, the subject matter of the final products, the pharmaceutical preparations, and the claims, are incorporated in the present application by reference to these publications. Preferred dipeptidyl peptidase IV inhibitors are also described in International Application Number WO 2004/037181, especially Examples 1 to 33, and more preferably the compounds described in claims 3 to 5. Preferred dipeptidyl peptidase IV inhibitors are the N-substituted adamantyl-amino-acetyl-2-cyano-pyrrolidines, N- (substituted glycyl) -4-cyano-pyrrolidines, N- (N-substituted glycol) -2-cyano-pyrrolidines, N-amino-acyl-thiazolidines, N-amino-acyl-pyrrolidines, L-allo-isoleucyl-thiazolidine, L-threo-isoleucyl-pyrrolidine, and L-allo-isoleucyl-pyrrolidine, 1 - [2 - [(5- cyano-pyridin-2-yl) -amino] -ethyl-amino] -acetyl-2-cyano- (S) -pyrrolidine, MK-431, and the pharmaceutical salts thereof. The most preferred dipeptidyl peptidase IV inhibitors are selected from [S] -1- [2- (5-cyano-2-pyridinyl-amino) -ethyl-amino] -acetyl-2-pyrrolidine-carbonitrile monohydrochloride, (S) -1 - [(3-hydroxy-1-adamantyl) -amino] -acetyl-2-cyano-pyrrolidine and L-threo-isoleucyl-thiazolidine (compound code according to Probiodrug: P32 / 98, as described above), MK-0431, 3- (amino-methyl) -2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinoline- carboxamide, and 2-. { [3- (amino-methyl) -2-isobutyl-4-phenyl-1-oxo-1,2-dihydro-6-isoquinolyl] -oxi} -acetamide, and optionally the pharmaceutical salts thereof. The monohydrochloride of [S] -1 - [2- (5-cyano-2-pyridinyl-amino) -ethyl-amino] -acetyl-2-pyrrolidine-carbonitrile and (S) -1 - [(3-hydroxy-1 -adminyl) -amino] -acetyl-2-cyano-pyrrolidine, are specifically disclosed in Example 3 of International Publication Number WO 98/19998, and in Example 1 of International Publication Number WO 00/34241, respectively . Particular preference is given to 1 -. { 2 - [(5-Cyano-pyridin-2-yl) -amino] -ethyl-amino} -acetyl-2- (S) -cyano-pyrrolidine (also referred to as [S] -1 - [2- (5-cyano-2-pyridinyl-amino) -ethyl-amino] -acetyl-2-pyrrolidin- monohydrochloride carbonitrile, or DPP728), of the Formula: in particular the dihydrochloride and monohydrochloride form thereof, 1 - [(3-hydroxy-1-adamyl) -amino] -acetyl-2-cyano-pyrrolidine, (S) (also referred to as (S) -1- [ (3-hydroxy-1-adamantyl) -amino] -acetyl-2-cyano-pyrrolidine, LAF237, or vildagliptin (INN)), of the Formula: and L-threo-isoleucyl-thiazolidine (Compound code according to Probiodrug: P32 / 98, as described above), MK-0431, GSK23A, saxagliptin, 3- (amino-methyl) -2-isobutyl-1 - oxo-4-phenyl-1,2-dihydro-6-isoquinolinecarboxamide, and 2-. { [3- (Amino-methyl) -2-isobutyl-4-phenyl] -1-oxo-1,2-dihydro-6-isoquinolyl] -oxi} -acetamide, and optionally in any case, the pharmaceutical salts thereof. DPP728 and LAF237 are disclosed in a specific manner in Example 3 of International Publication Number WO 98/19998, and in Example 1 of International Publication Number WO 00/34241, respectively. DPP728 and LAF237 can be formulated as described on page 20 of International Publication Number WO 98/19998, or in International Publication Number WO 00/34241, or in International Patent Application Number EP2005 / 000400 (application number) . Any of the substances disclosed in the aforementioned patent documents or scientific publications are included herein by reference, and are considered potentially useful as dipeptidyl peptidase IV inhibitors for carrying out the present invention. The dipeptidyl peptidase IV inhibitor to be used alone according to the present invention, it can be used in association with a vehicle. A vehicle in the present context is a tool (natural, synthetic, peptidic, non-peptidic), for example, a protein, which transports specific substances through the cell membrane, where it is embedded, and into the cells. Different vehicles are required (natural, synthetic, peptidic, non-peptidic) to transport different substances), because each one is designed to recognize only one substance, or a group of similar substances. Any means of detection known to the person skilled in the art can be used to detect the association of dipeptidyl peptidase IV with a vehicle, for example, by labeling the vehicle. More preferred are the dipeptidyl peptidase IV inhibitors and the orally active pharmaceutical salts thereof. The active ingredients (metformin or inhibitors of dipeptidyl peptidase IV inhibitors), or the pharmaceutically acceptable salts thereof, according to the present invention, can also be used in the form of a solvate, such as a hydrate, or including other solvents used for crystallization. In the present context, the terms "(S) -1 - [(3-hydroxy-1-andamantyl) -amino] -acetyl-2-cyano-pyrrolidine" or "LAF237" or "vildagliptin", are also intended to comprise any salt or form of glass of them. In a more preferred embodiment, the dipeptidyl peptidase IV inhibitor is added to the conventional diabetes treatment of patients whose disease was not adequately controlled by metformin alone: The present methods or uses are particularly useful for the prevention or delay of progress of conditions associated with type 2 diabetes or impaired glucose tolerance, in particular cardiovascular and microvascular conditions. Metformin, ie, N, N-dimethyl-imidocarbonymide diamide, is a known compound approved by the U.S. Food & Drug Administration (Administration of Food and Drug of the United States) for the therapeutic treatment of the diabetes. The compound and its preparation are disclosed, for example, in U.S. Patent No. 3,174,901, issued May 23, 1965. In the present context, the term "metformin" is also intended to comprise any salt or form of glass, especially the metformin hydrochloride salt. The term "before the evening meal", used herein, means the administration of the dipeptidyl peptidase IV inhibitor up to 1 hour, preferably up to 30 before the evening meal, for example 10, 5, or 1 minute before the evening meal. The term "with the food of the night", used in the present, means the administration of the dipeptidyl peptidase inhibitor IV in a concomitant manner with the evening meal, or optionally, for example, up to 1, 5, or 1 minute after the evening meal. Additionally, as used herein, "a daily dose" means the given dose within a 24-hour period. The term "prevention" means the prophylactic administration of the active ingredient to healthy patients to prevent the presentation of the conditions mentioned herein. Moreover, the term "prevention" means the prophylactic administration of this active ingredient to patients who are in a previous stage of the conditions to be treated. The term "progress delay", used herein, means the administration of the active ingredient, to patients who are in a previous stage of the condition to be treated, in whose patients a pre-form of the diagnosis is diagnosed. corresponding condition. The term "treatment" is understood as the management and care of a patient for the purpose of combating the disease, condition, or disorder. The term "treatment" also includes the "delay of progress" of the disease treated. As used herein, the term "patient" refers to an animal that is suffering from hyperglycemia, for example type 2 diabetes or impaired glucose metabolism. The preferred animal is a mammal, such as dogs, cats, horses, cattle, and Humans. It is preferred that the patient is a human being. In this field, the age of the preferred patient population is 45 years and older. The term "a patient with type 2 diabetes and baseline HbAlc> 8.0 percent" refers to a patient who has a glycosylated hemoglobin level, ie a higher HbAlc level of 8 percent, before treatment following the treatment method described here. The person skilled in the relevant art is absolutely qualified to select a relevant test model and protocols to prove the beneficial effects of the invention. The monitoring of glycemic status, as it is carried out by patients and health care providers, is well known in this field, as reported in Diabetes Care "Tests of Glycemia in Diabetes - American Diabetes Association" 2003 26: S106-108, and as described below. This publication is incorporated herein by reference in its entirety. The technical review of the American Diabetes Association should be consulted for more information (for example, Goldstein DE, Little RR, Lorenz RA, Malone Jl, Nathan D, Peterson CM: Tests of glycemia in diabetes (Technical Review). Diabetes Care 18: 896-909, nineteen ninety five). Test of glycated hemoglobin (GHb or HbAlc): GHb, also referred to as glycohemoglobin, hemoglobin glycosylated, HbA1c, or HbA ^ is a term used to describe a series of stable minor hemoglobin components formed slowly and non-enzymatically from hemoglobin and glucose. The rate of GHb formation is directly proportional to the concentration of environmental glucose. Because erythrocytes are freely permeable to glucose, the level of GHb in a blood sample provides a glycemic history of the previous 120 days, the average life span of erythrocytes. There are many different types of GHb assay methods available for clinical laboratory routine, for example HbA1c can be measured by high performance liquid chromatography (HPLC) using the ion exchange method in a BioRad Diamat analyzer. The methods differ considerably with respect to the measured glycated components, the interferences, and the non-diabetic interval. HbA1c has become the preferred standard for evaluating glycemic control. Referring to this test, the term "A1C test" will be used. Glucose level progress checks (eg, GSP, A1C, insulin assay) are well known to physicians and reported in the art, for example, by the American Diabetes Association. Preferably, the patient treated in the methods or uses described above, is suffering from hyperglycemia. From more preferably, the patient is suffering from hyperglycemia, is suffering from a disease selected from diabetes mellitus, type 1 diabetes, type 2 diabetes, insulin resistance type A, impaired glucose metabolism, impaired fasting glucose, or impaired tolerance to glucose. In a preferred embodiment, the patient is suffering from type 2 diabetes or impaired glucose tolerance. In another preferred embodiment, the patient treated is a patient whose disease was not adequately controlled by metformin alone. The structure of the active agents identified by code numbers, generic or commercial names, can be taken from the current edition of the standard compendium "The Merck Index", or from the databases, for example Patents International (for example, IMS World Publications). The corresponding content thereof is incorporated herein by reference. Any person skilled in the art is absolutely qualified to identify the active agents, and, based on these references, in the same way is able to manufacture and test the indications and pharmaceutical properties in conventional test models, both in vitro and in vivo. Preferably, the active ingredients (eg, the dipeptidyl peptidase IV inhibitor) are comprised in a pharmaceutical preparation (pharmaceutically acceptable carriers). The pharmaceutical compositions according to the invention can be prepared in a manner known per se, and are those suitable for enteral, such as oral or rectal, and parenteral administration to mammals (warm-blooded animals), including man, comprising a therapeutically effective amount of the pharmacologically active compound , alone or in combination with one or more pharmaceutically acceptable vehicles, especially suitable for enteral or parenteral application. Pharmaceutical preparations for enteral or parenteral administration, and also ocular, for example, are in unit dosage forms, such as coated tablets, tablets, capsules, or suppositories, and also ampoules. These are prepared in a manner that is known per se, for example, employing conventional mixing, granulating, coating, solubilizing, or freezing processes. Accordingly, pharmaceutical preparations for oral use can be obtained by combining the active compound with solid excipients, if desired a mixture that has been obtained is granulated, and if required or necessary, the mixture or the granulate is processed in tablets or cores of coated tablets after having added the appropriate auxiliary substances. The dosage of the active compound may depend on a variety of factors, such as the mode of administration, the homeothermic species, the age, and / or the individual condition. The corresponding active ingredient or a salt Pharmaceutically acceptable thereof, can also be used in the form of a hydrate, or can include other solvents used for crystallization. The exact dosage, of course, will vary depending on the compound employed, the mode of administration, and the desired treatment. The compound can be administered by any conventional route, non-orally, or preferably orally. In general, satisfactory results are obtained when the dipeptidyl peptidase IV inhibitor, especially vildagliptin, is administered in a daily dosage of about 0.01 to 50 milligrams / kilogram, with the most preferred doses being in the range of 0.1 to 50 milligrams / kilogram. . For higher mammals, an indicated daily dosage is in the range of about 0.01 to 100 milligrams / kilogram of the compound, conveniently administered in divided doses two to four times a day, in a unit dosage form containing, for example, about 0.1 to about 50 milligrams of the compound, in a sustained release form. Preferably, for the dipeptidyl peptidase IV inhibitors, especially vildagliptin, a total indicated daily dosage is in the range of 1 to 500 milligrams, preferably 10 to 200 milligrams of active ingredient. The daily oral dosage of vildagliptin is between 1 and 200 milligrams, preferably between 10 and 200 milligrams, for example of 10 milligrams, more preferably between 25 and 1 00 milligrams, for example 25 milligrams, or 30 or 40 or 50, 61, 70, 90, 100 milligrams. The highly preferred daily oral dosage of vildagliptin is between 50 and 1000 milligrams. Unit doses suitable for oral administration contain, for example, from about 25 to about 1000 milligrams of dipeptidyl peptidase IV inhibitors, especially vildagliptin, such as preferably 25, 50, or 100 milligrams. Appropriate doses for parenteral administration contain, for example, from about 1 to about 100 milligrams of the compound, for example from 1 to 50 milligrams. The dipeptidyl peptidase IV inhibitor can also be administered, for example, every day or twice a day. The compounds can be administered in a manner similar to known standards for uses in these utilities. The adequate daily dosage for a particular compound will depend on a number of factors, such as its relative activity potency. A person skilled in the relevant art is absolutely capable of determining the therapeutically effective dosage. The compound of the invention can be administered in free base form, or as a pharmaceutically acceptable quaternary ammonium or acid addition salt. These salts can be prepared in a conventional manner, and exhibit the same order of activity as the free forms. If these compounds have, for example, at least one basic center, can form acid addition salts. The corresponding acid addition salts can also be formed by having, if desired, a basic core additionally present. Compounds that have an acidic group (e.g., COOH) can also form salts with bases. In the present invention, the dipeptidyl peptidase IV inhibitor can also be in the form of a combination, which comprises an inhibitor of dipeptidyl peptidase IV in free or pharmaceutically acceptable salt form, and metformin or the pharmaceutically acceptable salt of the same, and optionally at least one pharmaceutically acceptable carrier, wherein the active ingredients can be administered in a simultaneous or sequential manner in any order, separately or in a fixed combination (in the same galenic formulation). A combined preparation comprising an inhibitor of dipeptidyl peptidase IV, in free or pharmaceutically acceptable salt form, and metformin or a pharmaceutically acceptable salt thereof, and optionally at least one, ie, one or more, for example 1 or 2 pharmaceutically acceptable carriers, for simultaneous, separate, or sequential use, is especially a "kit of parts" in the sense that the components, an inhibitor of dipeptidyl-peptidase IV in free or pharmaceutically acceptable salt form, and metformin or the pharmaceutically acceptable salt thereof, can be dosed independently, or by using different fixed combinations with amounts distinguished from the components, that is, at different points of time, or in a simultaneous manner. The parts of the kit of parts, then, for example, can be administered in a simultaneous or chronologically staggered manner, that is, at different points of time and with equal or different time intervals for any part of the kit of parts. A therapeutically effective amount of each of the components of the combination of the present invention may be administered simultaneously or in sequence and in any order, and the components may be administered separately or as a fixed combination. The invention has been described above with reference to the preferred embodiments, but, as will be appreciated by those skilled in the art, many additions, omissions, or modifications are possible, all within the scope of the claims set forth below. All patents and references of the literature cited in this specification are incorporated herein by reference in their entirety. In the case of inconsistencies, the present description will prevail, including definitions and interpretations: Example 1: Clinical study - Synopsis of the study and evaluation program. Research drug: 1) Vildagliptin: 100 milligram tablet 2) Paired placebo tablet. Study title: A two-period, double-blind, randomized, cross-over study to compare glycemic profiles in patients with type 2 diabetes after administration of 100 thousand igramos of vildagliptin once a day in the morning or in the morning. night. Objectives: The production of basal hepatic glucose (HGP) in type 2 diabetic patients is high, and the increase in HG P correlates closely with the severity of fasting hyperglycemia. The objective of this study is to explore whether the dosing regime given at night (for example, as once a day) may or may not result in a better suppression of HGP throughout the night, and consequently, result in better control of the glycemic profiles of 24 hours in addition to the FPG (fasting plasma glucose). Primary objective: To compare the effect of an oral dosage of 1 000 milligrams of vildagliptin, administered once a day in the morning against the night, on post-prandial glucose profiles for 24 hours, after 28 days of treatment. Secondary objectives: To compare the effect of 100 milligrams of vildagliptin given orally, either in the morning or at night, on fasting plasma glucose levels (FPG) after treatment during 28 days. To compare the effect of 1 00 milligrams of vildagliptin given orally, either in the morning or at night, on the levels of dipeptidyl-peptidase IV, GLP-1, glucagon, and insulin. To assess the safety and tolerability of 1 00 milligrams of vildagliptin given once a day at night. Design: This is a two-period, double-blind, randomized cross-over study. A total of 40 patients with type 2 diabetes are randomly selected (men and women), and at least 38 complete the study (if the number of patients who continue in the study drops to 38, any other discontinued patients should be replaced). Eligible patients participate in a two-day individual-blind placebo treatment (introductory period). After this, each patient is randomly selected to receive the following two treatments (AB or BA). Treatment A: One 100 milligram tablet of vildagliptin in the morning, one placebo tablet in the evening (28 days). Treatment B: One placebo tablet in the morning, and one 100 milligram tablet of vildagliptin in the evening (28 days). There is a 28-day selection period that includes a 21-day washout of the previous oral hypoglycemic agents, such as metformin and sulfonyl-urea. A sample of glucose is extracted fasting plasma (FPG) of each patient in the selection. Day -7 (during the wash), and at the baseline (Day -3). Patients who meet the inclusion / exclusion criteria are admitted to the study center on the night of Day -4. On Day -3 (following a 10-hour fast), baseline evaluations are carried out to confirm patient eligibility. On Day -2, patients begin the blind-individual placebo introduction period. Each patient is given placebo tablets twice a day for 2 days (Day -2 and Day -1); one tablet in the morning 30 minutes before breakfast, and one in the evening, 30 minutes before dinner. No matter where they are domiciled, patients consume standardized foods: breakfast starts at approximately 08:00 hours, lunch starts at approximately 12:00 hours, and dinner starts at approximately 1:00 p.m. On Day-1, the morning dose is administered followed by a fast overnight (10 hours). Patients consume a standard ADA breakfast 30 minutes after the dose, and blood sampling is done at the specified times to determine glucose, insulin, dipeptidyl-peptidase IV, GLP-1, and glucagon, up to 24 hours after the morning dose. Following this introductory period, eligible patients participate in two treatment periods of 28 consecutive days (outpatients), and one end of the study evaluation. The period of introduction is blind-individual; while the two treatment periods of 28 days They are double-blind. On Day 1, the first dose of the first treatment period is followed by overnight fasting (at least 10 hours). Patients consume a standard ADA breakfast 30 minutes following administration of the drug. Patients are discharged from the study center 4 hours after the dose, with guidance for dietary maintenance, adherence to the previous exercise regimen, outpatient medication for 28 days, instructions for outpatient dose administrations, a glucometer, an external patient diary, and a calendar marked with scheduled return appointments. Each patient receives two bottles of study medication - one contains the medication, which will only be taken in the morning, and the other bottle contains the study medication that will only be taken at night. During outpatient days, patients administer the morning and evening doses immediately before breakfast and dinner meals, respectively. Patients return to the study center for an interim safety assessment, a review of outpatient diaries, and a pill count once on Day 14 of each treatment period. In these appointments the compliance of the patients is evaluated through the counting of the drug. Patients who have stopped taking more than 6 percent (six doses) of the study medication are not allowed to continue in the study.

For pharmacokinetic and pharmacodynamic evaluations, patients return to the study center on the night of Day 26 of each treatment period, and will remain domiciled until the morning of Day 29. On Day 26, patients self-administer the dose of the night and eat dinner before arriving at the study site. On Day 28 of each treatment period, the morning dose is administered followed by a fast overnight (10 hours). Patients must consume a standard ADA breakfast (at 08:00 hours), 30 minutes after dosing (at 07:30 hours), and blood sampling is done at the specified times for vildagliptin, dipeptidyl- peptidase IV, GLP-1, glucose, insulin, and glucagon, up to 24 hours after the morning dose. It should be noted that pre-dose glucose levels are used on Day 28 of each treatment period to determine fasting plasma glucose. Samples of the HbAl c measurement are collected before dosing on Day 28 of each treatment period. The dose of the night is administered 30 minutes before dinner (dinner at 1 8:00 hours). Based on the results of the safety evaluations on Day 27 of the treatment period 1, patients who continue to meet the eligibility criteria initiate dosing for the treatment period 2, 1 day after the conclusion of the PD sampling for the period 1. The evaluations of the termination of the study are carried out following the last pharmacokinetic / pharmacodynamic evaluation in the treatment period 2 (Day 29). Table 1 provides an overview of the study. (a) Table 1 - Survey Overview Day Section (s) Study Study Requirements Selection Days -32 • Levels of 3-5 HbAl c are determined in the selection. • Fasting plasma glucose is determined in the selection and on Day -7. • Selection evaluations: medical history, concomitant medications, physical examination, vital signs, ECG, safety laboratory studies, pregnancy test, inclusion / exclusion criteria. • 21-day wash of previous hypoglycemic agents.

Line Days -4 • Patients are admitted in the base / period to -1 night of Day -4. of introduction • Baseline assessments are conducted on Day -3.

Section of the Day (s) Study Requirements Study - The inclusion / exclusion criteria are confi rmed. - Fasting plasma glucose. • Days -2 and -1: Patients are given placebo tablets (twice a day). • Day -1 (followed by a 1-hour fast): PD evaluations for 24 hours.

• Patients are given placebo tablets (twice a day). • Day -1 (following a fast Section of the Day (s) Study Requirements Study Patients are released 4 hours after dosing. • They receive the drug, the diary, and instructions. • External patient dosing during the remaining days of the study (Day 1, night dose, until Day 26, night dose).

Day 14 • Patients return to the study center. • Security evaluation. • Drug counting and diary review.

Days 1 5- • Dosing of patient 26 external. • Patients return to the study center on the night of Day 26 (patients are administered the night dose and eat dinner before arriving at the site of the Day Section (s) Study Study Requirements study) .

Day 27 • Patients are given standardized foods. • Security assessments. • Drug counting and diary review.

Day 28 • Morning dose after 10 hours of fasting. • Patients are given a standardized breakfast 30 minutes after dosing. • PK / PD evaluations for 24 hours.

Day 29 • PK / PD sampling for period 1 ends. • Following the last PK / PD sample, patients are downloaded with medication, diary, and instructions for the Day Section (s) Study Study Requirements Day 28 • Morning dose after 1 hour of fasting. • Patients are given a standardized breakfast 30 minutes after dosing. • PK / PD evaluations for 24 hours.

EOS Day 29 • The end of the study evaluations begins after the last PK / PD sample. • Patients are released from the study center following the end of study evaluations.

Only patients who continue to meet the inclusion criteria following safety evaluations on Day 27 receive medication for Treatment Period 2 at the time of discharge.

Number of patients: 40 (38 must complete all evaluations). Summary of criteria for inclusion: • Men or women (post-menopausal, surgically sterile, or using double-barrier method of contraception).

• Ages 18 to 75 years with type 2 diabetes. • Patients must be diagnosed with type 2 diabetes for at least 3 months. Patients should be otherwise in good health, as determined by medical history, physical examination, electrocardiogram, laboratory tests, and urinalysis. • Patients whose diabetes is controlled by diet and exercise alone, or who wish to undergo a three-week hypoglycemic wash. • Fasting plasma glucose between 110 and 240 milligrams / deciliter (between 6.0 and 13 millimoles / liter) in the selection and in the baseline. • HbA1c from 7.0 to 10 percent in the selection. • Body mass index < 35 kilograms / square meter. • Patients should wish to comply with all the requirements of the study, and provide written informed consent. Duration of treatment: 58 days (introduction period of 2 days plus two treatment periods of 28 days).

Pharmacokinetic evaluations: • Blood collection for the determination of vildaaliptina (1 milliliter of blood per sample, tubes with heparin (plasma)): Day 28 (Period 1) and Day 28 (Period 2): Before the dose, 0.5, 1 , 1.5, 2, 3, 5, 7, 10 (before the night dose), 10.5, 11, 11.5, 12, 13, 15, 17, and 24 hours after the morning dose. • Analytes, media, and methods: LAF237 in plasma by LC-MS / MS; LOO of approximately 2 nanograms / milliliter. • Pharmacokinetic parameters for vildagliptin: Cma, tma ?, Pharmacodynamic evaluations: 1. Activity of dipeptidyl-peptidase IV in plasma (sample of 1 milliliter of blood). • Day -1 (second day of the introduction placebo treatment), Day 28 (Period 1) and Day 28 (Period 2): Before the dose, 0.50, 0.75, 1, 1.25, 1.5, 2.5, 5.5, 10.5 ( before the evening meal), 10.75, 11, 1.5, 12.5, 15.5, and 24 hours after the morning dose. 2. GLP-1 in plasma (sample of 2 milliliters of blood). • Day -1 (second day of the introduction placebo treatment), Day 28 (Period 1) and Day 28 (Period 2): Before the dose, 0.583, 0.666, 0.75, 1, 1.25, 1.5, 2, 2.5, 3.5, . 5, 8.5, 10.5 (before dinner), 10,583,10,666, 10.75, 11, 11.25, 11.5, 12, 12.5, 14.5, 17.5 and 24 hours after the dose of the morning. 3. Glucagon (2 milliliters of blood per sample). • Day -1 (second day of introduction placebo treatment), Day 28 (Period 1) and Day 28 (Period 2): Before dose, 0.583, 0.666, 0.75, 1, 1.25, 1.5, 2, 2.5, 3.5, . 5, 8.5, 10.5 (before the evening meal), 10.583, 10.666, 10.75, 11, 1.25, 1.5, 12, 12.5, 14.5, 17.5 and 24 hours after the morning dose. 4. Insulin and glucose (2.5 milliliters of blood per sample). • Day -1 (second day of introduction placebo treatment), Day 28 (Period 1) and Day 28 (Period 2): Before the dose *, 0.5, 1, 1.25, 1.5, 1.75, 2, 2.5, 3 , 3.5, 4.5 (before lunch), 5, 5.25, 5.5, 6, 6.5, 7, 7.5, 8.5, 10.5 (before the evening dose and before dinner), 11, 11.25, 11.5, 11.75, 12, 12.5, 13, 13.5, 14.5, 17.5, 24 hours before the morning dose. * Samples before the dose on Day 28 of each treatment period are also used to determine fasting plasma glucose. Estimated total blood volume taken per patient: 672 milliliters Statistical methods 1. Sample size: The sample size for this study is determined based on a two-sided T-test sample with a 5 percent significance level , considering that the cross design is used, and the underlying null hypothesis is to test the equality of means against inequality for the point Primary pharmacodynamic endpoint (glucose AUE / 0-24)). Due to the lack of variability information about the pharmacodynamic end point, a range of variability entries is evaluated to provide information for the sample size required for the current study. A previous study using a dosing regimen twice daily showed that the coefficient of variation for intravenous glucose AU E (0-1 4) was approximately equal to 0.20. It is assumed that the variability of AUE (0-24) is greater than that of AUE (0-14). When the intra-patient coefficient of variation is not greater than 0.30, a sample size of 40 patients will ensure a power of 87 percent to detect a difference of 1 5 percent between the dosing regimens in the morning and at night ( see Table 2). (b) Table 2 - Statistical power to detect the real difference between the variability given for a sample size of 40 patients. 2. Statistical analysis: A variation analysis (ANOVA) is carried out on log-transformed pharmacodynamic variables using the PROC MIXED SAS procedure. The sources of variation included in the ANOVA model are the sequence, the patient (sequence), the period, and the treatment, with the patient (sequence) as a random effect. The dosage of the morning is the trial treatment, and the dosage of the night is the reference. Using the information of the ESTIMACIÓN (ESTÍMATE) of the PROX MIXED SAS procedure, the contrast between the test and reference treatments is constructed, to obtain the p-value, the estimated average difference, and the confidence interval (Cl) of the 95 percent for the test-reference difference at scale-log. The Anti-logs of the estimated mean difference and the 95 percent confidence interval are the proportion of the geometric mean, and the 95 percent confidence interval for the actual test-reference ratio. The results of the comparison are tabulated. Pharmacokinetic evaluations: Blood collection: All blood samples will be taken either through direct venipuncture or through a lodged cannula inserted into a vein in the forearm. For each scheduled LAF237 (vildagliptin) sample, a sample of 1 milliliter of blood is collected in a tube with sodium or lithium heparin. Samples will be collected according to the previously defined program presented in the Study Synopsis. Handling blood samples: Immediately after each blood tube is removed, it should be gently inverted several times to ensure mixing of the contents of the tube (eg, anticoagulant). Prolonged contact of the sample with the rubber stopper is avoided. The erect tube is placed in a grid of test tubes (for example, surrounded by ice or at room temperature) until centrifugation. Within 15 minutes, the sample is centrifuged between 3 ° C and 5 ° C for 1 5 minutes at approximately 2,500 revolutions per minute. Transfer all available plasma to a polypropylene screw cap tube, and freeze at -70 ° C or less within 60 minutes of venipuncture. Analytical methods: Analytes, media, and methods: Vildagliptin in plasma by LC-MS-MS; LOQ to 2 nanog ramos / mi I liter. Pharmacodynamic evaluations: Samples will be collected according to the previously defined program presented in the Study Synopsis. The study site should provide the actual date and time of the sample collection, and should document in the appropriate CRF. A separate document will be provided illustrating the procedures for sample collection, processing, and shipment, as complements to the Protocol. - Glucose, insulin, and glucagon samples: Glucose, insulin, and glucagon are measured in plasma. For each sample collection scheduled for the glucose and insulin test, a sample of 2.5 milliliters of blood is collected in a tube containing heparin (for example, BD - 3 milliliters of PST, plasma separating tubes and heparin). The erect tube is placed in a grid surrounded by ice until centrifugation. Within 15 minutes after collection, the sample is centrifuged at 3 ° C to 5 ° C for 15 minutes at approximately 2,500 revolutions per minute. Transfer all available plasma (at least 1.0 milliliters) to a polypropylene screw cap tube, and freeze at -80 ° C or less within 60 minutes of venipuncture. For each sample collection scheduled for glucagon analysis, a sample of 2 milliliters of blood is collected in an icy glass tube containing aprotinin. Gently invert each tube several times to mix the contents of the tube, avoiding prolonged contact of the sample with the rubber stopper. The erect tube is placed in a grid surrounded by ice until centrifugation. Within 1 5 minutes of collection, the sample is centrifuged between 3 ° C and 5 ° C for 1 5 minutes at approximately 2,500 revolutions per minute. Using a glass pipette, transfer all available plasma (at least 0.75 milliliters in total) to a glass transfer tube supplied by CRO, and freeze at -8 ° C or less within 60 minutes of venipuncture. A separate document will be provided that illustrates the collection and management of pharmacodynamic samples. Plasma GLP-1 level: For each sample collection scheduled for GLP-1 analysis, a sample of 2 milliliters of blood is collected in a tube containing potassium EDTA, to which 0.1 milliliters of a solution has been added. of Diprotin A 3 m M. Gently invert each tube several times to mix the contents of the tube, avoiding prolonged contact of the sample with the rubber stopper. The erect tube is placed in the grid surrounded by ice until centrifugation. Within 15 minutes of collection, the sample is centrifuged at 3 ° C to 5 ° C for 15 minutes at approximately 2,500 revolutions per minute. Transfer all available plasma (should be approximately 1.3 milliliters in total) to a polypropylene screw cap tube, and freeze at -70 ° C or less within 60 minutes of venipuncture.

Plasma samples for inhibition of the dipeptidyl peptidase IV enzyme: For each sample collection programmed for the enzymatic analysis of dipeptidyl peptidase IV, a sample of 1 milliliter of blood is collected in a tube containing potassium EDTA. Gently invert several times to mix the contents of the tube. A prolonged contact of the sample with the rubber stopper is avoided. The erect tube is placed in a grid surrounded by ice until centrifugation. Within 15 minutes after collection, the sample is centrifuged at 3 ° C to 5 ° C for 15 minutes at approximately 2,500 revolutions per minute. Transfer all available plasma to a polypropylene screw cap micro-tube, and freeze at -70 ° C or less within 60 minutes of venipuncture. HbAlc: HbAlc is measured by the clinical laboratory associated with the study site, in a manner concurrent with the blood chemistry analysis in the selection (the same blood sample can be used). Additional blood samples are taken for HbAlc analysis before dosing on day 28 of each treatment period. - Fasting plasma glucose (FPG): Fasting blood glucose levels are carried out in the clinical laboratory associated with the study site during the selection, Day -7 (during washing), and in the baseline (Day 3). It should be noted that glucose levels are used before the dose on Day 28 of each treatment period to determine plasma glucose on an empty stomach. Analysis of pharmacodynamic data: Pharmacodynamic variables: All patients who carry out the study with evaluable pharmacodynamic evaluations (PD) are included in the data analysis. The pharmacodynamic responses are explored through graphic representations. The levels of dipeptidyl-peptidase IV, GLP-1, glucagon, glucose, and insulin in plasma are measured as the pharmacodynamic variables. The plasma concentrations of these variables are plotted against time, and the pharmacodynamic response is explored by inspection of the graphic representations. As appropriate, it is calculated from the value before the dose or from the baseline for each subject at each point of time. The percent inhibition of dipeptidyl peptidase VI activity is calculated, and plotted over time for each subject during each treatment period. The areas below the curve of the effect against time (AUE) for GLP-1 are calculated, glucagon, glucose, and insulin when considered necessary. When considered appropriate, the peak effect (Emax) and the time to peak effect (Tma x) are evaluated for each pharmacodynamic variable. Statistical methods for the pharmacodynamic analysis: A variation analysis (ANOVA) is carried out on the log-transformed pharmacodynamic variables, using the procedure PROC MIXED SAS. The sources of variation included in the ANOVA model are the sequence (patient), the period, and the treatment, with the patient (sequence) as a random effect. The dosage of the morning is the trial treatment, and the dosage of the night is the reference. Using the ESTIMATION information (ESTÍMATE) of the PROC MIXED SAS procedure, the contrast between the test and reference treatments is constructed, to obtain the p-value, the estimated average difference, and the confidence interval (Cl) of 95%. cent for the test-reference difference at scale-log. The anti-logs of the estimated mean difference and the 95 percent confidence interval are the proportion of the geometric mean, and the 95 percent confidence interval for the actual test-reference ratio. The results of the comparison are tabulated.

Results: The administration of vildagliptin before or with the evening meal provides additional pharmacokinetic benefits, especially pharmacodynamics. Especially the resulting data show an unexpected additional benefit on the reduction of the HGP during the night, especially in patients with more severe type 2 diabetes, that is, with the glycosylated hemoglobin of the baseline (HbAl c) < 8.0 percent.

Claims (10)

1. A method for treating a patient suffering from hyperglycemia, wherein vildagliptin or a salt thereof is administered to this patient before or with night food.

2. The use of vildagliptin or a salt thereof, for the manufacture of a medicament for the treatment of hyperglycemia, wherein the vildagliptin or a salt thereof is administered to this patient before or with the evening meal.

3. A method for reducing the production of nocturnal hepatic glucose in a patient suffering from hyperglycemia, wherein vildagliptin or a salt thereof is administered to this patient before or with the evening meal.

4. The use of vildagliptin or a salt thereof, for the manufacture of a medicament for reducing the production of nocturnal hepatic glucose in a patient suffering from hyperglycemia, wherein vildagliptin or a salt thereof is administered to this patient before or with the food of the night.

5. A method or use according to any of claims 1 to 4, wherein the patient is suffering from type 2 diabetes.

6. A method or use according to any of claims 1 to 5, wherein the patient is suffering from type 2 diabetes with baseline HbAlc > 0 percent.

7. A method or use according to any of the claims 1 to 6, wherein they are administered between 25 milligrams and 1 00 milligrams, or between 50 milligrams and 1 00 milligrams of vildagliptin or a salt thereof, before or with the evening meal.

8. A method or use according to any of claims 1 to 5, wherein 25 milligrams, 50 milligrams, or 100 milligrams of vildagliptin or a salt thereof, is administered before or with the evening meal.

9. A method or use according to any of claims 1 to 8, wherein a daily dosage of January 00 mg of vildagliptin or a salt thereof is administered to the patient.

10. A method for reducing the production of nocturnal hepatic glucose in a patient suffering from hyperglycemia, wherein at least 1 00 milligrams of vildagliptin or a salt thereof is administered before or with the morning meal, or before or with lunch. eleven . The use of vildagliptin or a salt thereof, for the manufacture of a medicament for reducing the production of nocturnal hepatic glucose in a patient suffering from hyperglycemia, wherein at least 1 00 milligrams of vildagliptin or a salt of the same to this patient before or with the food in the morning, or before or with lunch. 1 2. A method or use according to any of claims 1 to 11, wherein the patient is suffering from type 2 diabetes 13. A method or use according to claim 12 wherein the patient is suffering from type 2 diabetes, with HbAlc base line > 8.0 percent. A method or use according to any of claims 10 to 13, wherein between 100 and 150 milligrams of vildagliptin or a salt thereof is administered to this patient before or with the morning meal, or before or with lunch. 15. A method or use according to any of claims 10 to 13, wherein 100 and 150 milligrams of vildagliptin or a salt thereof is administered to this patient before or with the morning meal, or before or with the patient. lunch. 16. A method or use according to any of claims 10 to 15, wherein vildagliptin or a salt thereof is administered in combination with metformin. 17. A method or use according to any of claims 10 to 16, wherein vildagliptin or a salt thereof is administered in combination with 250 milligrams, 500 milligrams, 750 milligrams, 850 milligrams, or 1,000 milligrams of metformin. 18. A method or use according to any of claims 10 to 17, wherein metformin is administered with the evening meal. 19. A method or use according to any of the preceding claims, wherein vildagliptin or a salt thereof is administered approximately 30 minutes before dinner.